Ring expansion approach for the synthesis of the (3S,4S)-hexahydroazepine core of balanol and ophiocordin

Article abstract of DOI:10.1016/j.tet.2003.09.089

A new and efficient formal total synthesis of (3S,4S)-balanol, a potent protein kinase C inhibitor, was accomplished from tri-O-acetyl-D-glucal. Balanol and ophiocordin consists of a chiral hexahydro azepine-containing fragment and a benzophenone fragment. The azepine core was prepared in chiral form through intramolecular aza Wittig reaction. A triphenylphosphine mediated ring expansion process was employed to form the seven-membered nitrogen heterocycle. The aldehyde equivalent key intermediate was treated with triphenylphosphine to give the azepine core. To demonstrate the applicability of the new route, a synthesis of the balanol is described.

Full text of DOI:10.1016/j.tet.2003.09.089

Tetrahedron 59 (2003) 10325–10329
Ring expansion approach for the synthesis of the
(3S,4S)-hexahydroazepine core of balanol and ophiocordinq
*
J. S. Yadav and Ch. Srinivas
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 12 July 2003; revised 1 September 2003; accepted 26 September 2003
Abstract—A new and efficient formal total synthesis of (3S,4S)-balanol, a potent protein kinase C inhibitor, was accomplished from tri-O-
acetyl-D-glucal. Balanol and ophiocordin consists of a chiral hexahydro azepine-containing fragment and a benzophenone fragment. The
azepine core was prepared in chiral form through intramolecular aza Wittig reaction. A triphenylphosphine mediated ring expansion process
was employed to form the seven-membered nitrogen heterocycle. The aldehyde equivalent key intermediate was treated with
triphenylphosphine to give the azepine core. To demonstrate the applicability of the new route, a synthesis of the balanol is described.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
involving PKC, but may also result in the introduction of
novel drugs with considerable therapeutic value. Due to its
high inhibitory activity in the nanomolar range, combined
structural novelty and low availability of the compound has
generated substantial interest in the development of
synthetic approaches to the natural material and related
structures. The synthetic community responded quickly to
the challenge of preparing balanol and analogues.
Systematic structural modifications of balanol were carried
out for the development of promising analogues13 with
therapeutic applications. Modification of the azepine ring
system resulted in several interesting lead compounds with
potent enzyme and cellular activity during the continuing
lead optimization study at Sphinx pharmaceuticals, now a
part of Eli Lilly.14
Protein kinase C (PKC) closely related to a family of core
enzymes (serine/threonine specific protein kinases), is a key
element in the wide range of cellular responses including
oncogenesis and inflammation.1,2 It can be activated by
diacylglycerol3 or tumor promoting phorbol ester,4,5 and it
has the ability to phosphorylate lipocortin.6,7 Protein
phosphorylation mediated by PKC is a critical step in the
signal transduction cascades controlling processes such as
cellular proliferation and gene expression,8 and the enzyme
has been implicated in the progression of a wide variety of
diseases, such as cancer, cardiovascular disorders, asthma,
diabetes, central nervous system dysfunction, inflammation,
rheumatoid arthritis and HIV infection. Consequently, the
identification of potent and selective PKC inhibitors may
not only serve to further illuminate signal transduction
pathways but also may result in the development of novel
drug with a unique therapeutic approach to these diseases.9
Although several inhibitors of PKC have been reported,10
they are either highly toxic or not very potent.
Balanol 1, a metabolite which is produced in trace amounts
by the fungus Verticillium balanoides11 and Fusarium
merismoides,12 selectively and potently inhibited human
PKC enzymes a, b-I, b-II, g, d, 1, and h with an IC50 value
of 4–9 nM. Such an endeavor may not only provide useful
tools for illuminating signal transduction pathways
We have recently provided two efficient approaches
including shortest route to the (3R,4R)-hexahydroazepine
ring of balanol.18m Considerable modifications of the
azepine ring of the balanol can be tolerated with certain
cases resulting in an increase in biological activity. Hence,
q IICT communication number: 021101.
Keywords: balanol; ophiocordin; ring expansion.
*
Corresponding author. Tel.: þ91-40-27193434; fax: þ91-40-27160512;
e-mail: yadav@iict.ap.nic.in
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.089

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in continuation of our two formal total syntheses of (3R,4R)-
balanol, we herein describe a novel and efficient approach
for the synthesis of the (3S,4S)-azepine segment of balanol
and its regio isomer, antibiotic ophiocordin15 2 from tri-O-
acetyl-D-glucal. Balanol consists of two distinct structural
domains, a chiral hexahydroazepine-containing fragment
and a benzophenone fragment (Scheme 1).
Scheme 1.
Total syntheses of balanol were achieved by Nicolaou’s
group and by researchers at Sphinx and at Rhone-Poulenc
Rorer.16 The hexahydroazepine has been targeted in several
formal synthesis of balanol17 Our synthetic approach
includes the preparation of the (3S,4S)-hexahydroazepine
segment 4 through ring expansion of six-membered ring
into seven-membered ring using triphenylphosphine.
Scheme 2. Reagents and conditions: (a) t-BuOH, CH2Cl2, BF3·Et2O, 108C
(95%); (b) K2CO3, MeOH/H2O, rt (quantitative); (c) H2, Pd/C, EtOAc, rt
(92%); (d) p-TsCl, TEA, CH2Cl2, 08C then NaN3, DMF, 808C (90%);
(e) BnBr, NaH, THF, Bu4NI, rt (97%); (f) 60%AcOH, cat. dil. H2SO4, 708C
(95%); (g) TPP, Toluene, reflux, then toluene was removed, NaBH4,
MeOH, 08C, then (Boc)2O, TEA, rt (75%); (h) Tf2O, 2,6-lutidine, CH2Cl2,
08C, then NaN3, DMF (91%) (or) MsCl, TEA, CH2Cl2, 08C, then NaN3,
DMF, 808C (97%); (i) H2, Pt2O, EtOAc, rt, then p-benzyloxybenzoyl
chloride, TEA, CH2Cl2, 08C to rt (53%).
2. Results and discussion: ring expansion approach and
chiral hexahydroazepine synthesis
Strategies involving aza Wittig reactions have become
useful tools in organic synthesis. Particularly, the intra-
molecular aza Wittig approach could be applied for the
construction of various type of cyclic nitrogen heterocycles.
The synthesis of 4 began with tri-O-acetyl-D-glucal 5 as
shown in Scheme 2. Accordingly tri-O-acetyl-D-glucal was
obtained from D-glucose by a known literature procedure.18
hydroazepine moiety 4 of balanol is very straightforward.
Hydrogenation of 13 in ethyl acetate liberated the amino
group from its azido surrogate, and simultaneously
deprotected the benzyl ether function with PtO2. Acylation
of the resulting amino alcohol with p-benzyloxy-
benzoylchloride delivers the product 4, which is directly
amenable to the total synthesis of balanol.
Ferrier rearrangement of tri-O-acetyl-D-glucal 5 with tert-
butyl alcohol in DCM provided the desired tert-butyl ether
6. Removal of acetyl groups from 6 with K2CO3 in aq.
methanol afforded the free diol 7 in quantitative yield. The
double bond in the diol was hydrogenated with 5% Pd/C in
ethyl acetate to afford the saturated diol 8 in good chemical
yield (92%). The primary hydroxyl of the diol 8 was
tosylated, followed by the displacement with NaN3 in DMF
to furnish the azido alcohol 9. The free hydroxy function-
ality of the azidoalcohol was protected as its benzyl ether
using BnBr, NaH to give compound 10. The cleavage of the
tert-butyl ether group from 10 with 60% AcOH, and cat. dil.
H2SO4, afforded the key intermediate 11. Aldehyde
equivalent 11 was treated with TPP in toluene at reflux
temperature. After completion of the reaction toluene was
removed and the resulting crude imine was subjected to
reduction with NaBH4 in methanol.
3. Conclusion
In summary we have described efficient synthesis of the
balanol heterocycle from tri-O-acetyl-D-glucal which
incorporated a novel ring expansion process to the seven-
membered azepine core. It is noteworthy that the afore-
mentioned synthetic strategy for the hexahydroazepine
fragment is particularly suitable for the analogue
generation. This approach offers readily available starting
materials at low cost and simple experimental conditions.
Further work is currently ongoing.
4. Experimental
4.1. General
The resultant amine was protected in situ with BOC2O, TEA
to afford the azepine segment 12. Subsequent conversion of
its secondary alcohol into an azido group to get 13 was
achieved via treatment with Tf2O and 2,6-lutidine followed
by NaN3 displacement. Alternatively the desired product 13
can be obtained with MsCl, TEA followed by NaN3
treatment. The final elaboration of the targeted hexa-
Unless otherwise stated, all reactions were carried out under
nitrogen and dry glassware. THF was dried and freshly
distilled over sodium/benzophenone. Dichloromethane and
DMF were freshly distilled over P2O5 and CaSO4,
respectively. Reactions were monitered by thin-layer

J. S. Yadav, Ch. Srinivas / Tetrahedron 59 (2003) 10325–10329
10327
chromatography (TLC) analysis. IR spectra were recorded
1
IR (Neat) (cm21): 3428, 2927, 1726, 1176, 1044, 770. Mass:
[M2zC4H8]þ(C6H12O4) theoretical mass 148.0735, found
148.0726. Anal. calcd for C10H20O4: C 58.80, H 9.87,
found: C 58.58, H 9.92.
as neat thin film on Perkin–Elmer I spectrometer. H and
13C were recorded on Varian Gemini-200 MHz or Avance-
300 MHz spectrophotometers in CDCl3 using TMS as
internal standard.
4.1.4. 2-Azidomethyl-6-(tert-butoxy)-(2R,3S)-tetra-
hydro-2H-3-pyranol (9). To a well-stirred solution of 8
(2 g, 9.8 mmol) in dry DCM (25 ml) was added triethyl-
amine (1.36 ml, 9.8 mmol) followed by p-toluene sulphonyl
chloride (1.86 g, 9.8 mmol) at 08C. The reaction mixture
was stirred for 6 h at the same temperature. The CH2Cl2 was
removed under reduced pressure and crude sulphonate was
dissolved in dry DMF (7 ml) and treated with sodium azide
(3.18 g, 49 mmol). The reaction mixture was stirred further
for 12 h at 808C. After completion of the reaction, it was
extracted with ether (3£50 ml). Combined organic layer
was washed with water, brine and dried over Na2SO4. After
removing the volatiles under reduced pressure, crude azide
was purified by column chromatography with 7% EtOAc in
hexane as eluent to furnish 9 (2 g, 90% yield) as a colorless
4.1.1. 6-(tert-Butoxy)-3-methylcarbonyloxy-(2R,3S)-3,6-
dihydro-2H-2-pyranylmethyl acetate (6). Compound 5
(12.5 g, 45.9 mmol) and t-butyl alcohol (7 ml, 91.9 mmol)
were dissolved in dry DCM (100 ml) cooled in an ice bath
(108C) and treated with catalytic BF3·Et2O (0.3 ml). After
stirring the reaction mixture for 12 h at ambient tempera-
ture, reaction mixture was quenched with saturated sodium
bicarbonate, and extracted with DCM. Organic layer was
washed with water, brine and dried over Na2SO4. Volatiles
were removed under reduced pressure. Crude compound
was purified using column chromatography with 3%
EtOAc, in hexane as eluent to furnish 6 (12.25 g, 95%
yield) as a pale yellow liquid. [a]D¼þ100.69 (c 0.75,
CHCl3). 1H NMR (CDCl3, 200 MHz): d 1.25 (s, 9H,
OC(CH3)3), 2.05 (s, 6H, OCOCH3, OCOCH3), 4.10 (m, 3H,
CH2OAc, HCO), 5.20 (m, 2H, CHOt-Bu, CHOAc), 5.75 (m,
2H, CHvCH). 13C NMR (CDCl3, 100 MHz): d 170.9,
170.5, 129.9, 128.4, 89.2, 75.5, 66.8, 65.5, 63.5, 29.0, 21.2,
21.0. IR (Neat) (cm21): 2976, 1746, 1436, 1370, 1236,
1195, 1099, 1044, 1025, 982, 891, 774. Mass: [M2zotBu]þ
(C10H13O5) theoretical mass 213.0763, found 213.0770.
[M2zotBu–AcOH]þ(C8H9O3) theoretical mass 153.0551,
found 153.0543. Anal. calcd for C14H22O6: C 58.73, H 7.74,
found: C 58.64, H 7.83.
1
liquid. [a]D¼þ69.91 (c 0.75, CHCl3). H NMR (CDCl3,
200 MHz): d 1.20 (s, 9H, OC(CH3)3), 1.70 (m, 2H, CH2),
1.80 (m, 2H, CH2), 3.40 (m, 3H, CH2N3, CHOH), 3.75 (m,
1H, HCO), 5.05 (bs, 1H, OCHO). 13C NMR (CDCl3,
100 MHz): d 90.4, 74.4, 72.3, 67.6, 52.2, 30.8, 28.6, 27.3. IR
(Neat) (cm21): 3415, 2972, 2100, 1590, 1440, 1348, 1288,
1196, 1121, 1042, 989, 922, 590. Mass: [M2C4H8]þ
(C6H11N3O3) theoretical mass 173.0800, found 173.0808.
Anal. calcd for C10H19N3O3: C 52.39, H 8.35, N 18.33,
found: C 52.02, H 8.13, N 18.02.
4.1.2. 6-(tert-Butoxy)-2-hydroxymethyl-(2R,3S)-3,6-
dihydro-2H-3-pyranol (7). A well-stirred solution of 6
(5 g, 17.45 mmol) in MeOH/H2O (50 ml) was added K2CO3
(7.25 g, 52.4 mmol) at room temperature. After stirring for
12 h, the reaction mixture was filtered off through a sintered
funnel. Methanol was removed under reduced pressure and
compound was extracted with EtOAc, to give 7 (3.5 g) as a
colorless solid in quantitative yield. [a]D¼þ38.63 (c 0.5,
CHCl3). 1H NMR (CDCl3, 200 MHz): d 1.25 (s, 9H,
OC(CH3)3), 3.80 (m, 3H, CH2OAc, HCO), 4.10 (m, 1H,
CHOH), 5.25 (bs, 1H, OCHO), 5.60 (m, 1H, CHv), 5.90
(m, 1H, CHv). 13C NMR (CDCl3, 100 MHz): d 132.9,
127.6, 88.9, 75.2, 71.0, 63.8, 62.5, 28.8. IR (Neat) (cm21):
3418, 2975, 2927, 1645, 1368, 1193, 1042, 771. Mass:
[M2zotBu]þ(C6H9O3) theoretical mass 129.0551, found
129.0549. Anal. calcd for C10H18O4: C 59.39, H 8.97,
found: C 59.21, H 9.07.
4.1.5. 2-Azidomethyl-3-benzyloxy-6-(tert-butoxy)-
(2R,3S)-tetrahydro-2H-pyran (10). To a well-stirred
suspension of freshly activated NaH (0.225 g,
9.375 mmol) in dry THF (5 ml), a solution of 9 (1.75 g,
7.6 mmol) in dry THF was added dropwise at 08C. After
30 min, BnBr (1.15 ml, 9.9 mmol) and catalytic Bu4NI
(0.28 g, 0.75 mmol) were added and the reaction mixture
was stirred for 3 h. Then aq. NH4Cl solution was added to
quench the reaction, THF layer was separated and the
aqueous layer was extracted with ether (3£30 ml). The
combined organic layer was washed with water, brine and
dried over Na2SO4. After removing the volatiles under
reduced pressure, crude benzyl ether was purified by column
chromatography with 3% EtOAc in hexane as eluent to
furnish 10 (2.3 g, 95% yield) as a colorless liquid.
[a]D¼þ106.01 (c 1, CHCl3). 1H NMR (CDCl3,
300 MHz): d 1.25 (s, 9H, OC(CH3)3), 1.65–2.05 (m, 4H,
CH2–CH2), 3.25–3.45 (m, 3H, CH2N3, CHOBn), 3.95 (m,
1H, HCO), 4.40 (d, 1H, J¼12 Hz, CH2Ph), 4.60 (d, 1H,
J¼12 Hz, CH2Ph), 5.05 (bs, 1H, OCHO), 7.25 (m, 5H,
C6H5). 13C NMR (CDCl3, 100 MHz): d 138.5, 128.5, 128.4,
127.6, 127.5, 90.2, 70.4, 70.2, 70.1, 50.2, 30.1, 28.2, 20.3.
IR (Neat) (cm21): 2974, 2100, 1456, 1364, 1270, 1195,
1097, 1005, 914, 739, 698. Mass: [M2C4H9ON2]þ(C13-
H16NO2) theoretical mass 218.1181, found 218.1175. Anal.
calcd for C17H25N3O3: C 63.93, H 7.89, N 13.16, found: C
63.91, H 7.75, N 12.84.
4.1.3. 6-(tert-Butoxy)-2-hydroxymethyl-(2R,3S)-tetra-
hydro-2H-3-pyranol (8). Pd/C (5%, w/w) is added to a
solution of compound 7 (1.5 g, 7.42 mmol) in dry ethyl
acetate (7 ml), and the resulting suspension is stirred under
H2 for 12 h. The catalyst is filtered off through a pad of
celite, which is carefully rinsed with ethyl acetate in several
portions. Evaporation of the solvent under reduced pressure
and column chromatographed with 25% EtOAc in hexane as
eluent furnished 8 (1.4 g, 92% yield) as a colorless viscous
1
liquid. [a]D¼þ116.22 (c 0.5, CHCl3). H NMR (CDCl3,
200 MHz): d 1.25 (s, 9H, OC(CH3)3), 1.70 (m, 2H, CH2),
1.85 (m, 2H, CH2), 3.50–3.70 (m, 4H, CH2OH, HCO,
CHOH), 5.05 (bs, 1H, OCHO). 13C NMR (CDCl3,
100 MHz): d 90.5, 74.2, 72.5, 69.9, 62.7, 30.9, 28.8, 26.8.
4.1.6. 6-Azidomethyl-5-benzyloxy-(5S,6R)-tetrahydro-
2H-2-pyranol (11). Compound 10 (1.5 g, 4.7 mmol) was
treated with 60% acetic acid (15 ml) and catalytic 50%
sulphuric acid (0.2 ml). The reaction mixture was warmed at

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J. S. Yadav, Ch. Srinivas / Tetrahedron 59 (2003) 10325–10329
708C using water bath for 30 min. After completion of
reaction it was quenched with saturated sodium bicarbonate
solution and extracted with EtOAc. Organic layer was
washed with water, brine and dried over Na2SO4. Evapor-
ation of the solvent under reduced pressure and was column
chromatographed with 15% EtOAc in hexane as eluent
2H, CH2), 1.95 (m, 2H, CH2), 2.95–3.82 (series of
multiplets, 6H, CH2NBOC, CH2NBOC, CHN3, CHOBn),
4.60 (m, 2H, CH2Ph), 7.30 (m, 5H, C6H5). 13C NMR
(CDCl3, 100 MHz): d 150.5, 137.8, 128.3, 127.8, 127.7,
82.7, 80.1, 71.5, 65.2, 64.2, 45.4, 28.3, 27.2, 21.7. IR (Neat)
(cm21): 2932, 2104, 1693, 1410, 1257, 1164. FABMS: m/z
347 (Mþ1). Anal. calcd for C18H26N4O3: C 62.41, H 7.56,
N 16.17, found: C 62.24, H 7.32, N 16.02.
1
furnished 11 (1.15 g, 95% yield) as a colorless liquid. H
NMR (CDCl3, 200 MHz): d 1.80 (m, 4H, CH2–CH2), 3.40
(m, 3H, CH2N3, CHOBn), 4.00 (m, 1H, HCO), 4.40 (d, 1H,
J¼10.4 Hz, CH2Ph), 4.60 (d, 1H, J¼10.4 Hz, CH2Ph), 5.25
(bs, 1H, OCHO), 7.30 (m, 5H, C6H5). IR (Neat) (cm21):
3416, 2938, 2121, 1725, 1632, 1496, 1455, 1351, 1289,
1219, 1106, 989, 903, 817, 749, 703.
4.1.9. tert-Butyl 3-(4-benzyloxy phenyl carboxamido)-4-
hydroxy-(3S,4S)-azepane-1-carboxylate (4). PtO2 (5%,
w/w) is added to a solution of compound 13 (110 mg,
0.317 mmol) in ethyl acetate (5 ml), and the resulting
suspension is stirred under H2 atmosphere for 14 h. The
catalyst was filtered off through a pad of celite. Evaporation
of the solvent provides amine, which is used in the
subsequent step without further purification. The benzyloxy
benzoyl chloride (77 mg, 0.317 mmol) is added to a solution
of crude amine prepared as described above. After stirring
for 2 h at room temperature the reaction mixture was
extracted with ethyl acetate. After usual workup, solvent
was evaporated under reduced pressure. Purification of the
crude product by 50% ethylacetate in hexane provided the
title compound 4 (73 mg, 53% over both steps). [a]D¼þ2.3
(c 0.9, CH3OH). 1H NMR (CDCl3, 200 MHz): d 1.30 (s, 9H,
OC(CH3)3), 1.57–1.95 (m, 4H, CH2–CH2), 2.60 (m, 1H,
CHNHCO), 3.45 (m, 1H, CH2NCO), 3.70 (m, 1H,
CH2NCO), 4.30–4.45 (m, 3H, CHOH, CH2NCO), 5.10 (s,
2H, CH2Ph), 6.98 (d, 2H, J¼8.8 Hz, COC6H4–), 7.20–7.47
(m, 5H, C6H5), 7.95 (d, 2H, J¼8.8 Hz, COC6H4–), 8.09 (s,
1H, NHCO). FABMS: m/z 441 (Mþ1). Anal. calcd for
C25H32N2O5: C 68.16, H 7.32, N 6.36, found: C 68.04, H
7.18, N 6.04.
4.1.7. tert-Butyl 4-benzyloxy-3-hydroxy-(3R,4S)-azi-
pane-1-carboxylate (12). To a stirred solution of 11 (1 g,
3.8 mmol) in dry toluene (15 ml) was added triphenyl
phosphene (1.49 g, 5.7 mmol). The reaction mixture was
stirred under reflux for 12 h. Evaporation of the solvent
provide the crude imine, which was used in the subsequent
step without further purification. The crude imine was
dissolved in anhydrous methanol (10 ml) cooled to 08C and
treated with sodium borohydride (0.15 g, 3.95 mmol). The
reaction mixture was stirred for 5 h at room temperature.
The resulting secondary amine was protected in situ with
(Boc)2O (1 g, 4.55 mmol) and triethyl amine (0.79 ml,
5.7 mmol) at room temperature. After stirring for 6 h at
ambient temperature volatiles were removed under reduced
pressure. The crude azepine compound 12 was extracted
with ethyl acetate and washed with water, brine and dried
over Na2SO4. Evaporation of the solvent under reduced
pressure and column chromatographed with 7% EtOAc in
hexane as eluent furnished 12 (0.9 g, 75% yield from 10) as
1
a colorless liquid. [a]D¼þ35.2 (c 0.9, CHCl3). H NMR
(CDCl3, 300 MHz): d 1.45 (s, 9H, OC(CH3)3), 1.50–2.10
(m, 4H, CH2–CH2), 2.90–3.85 (series of multiplets, 6H,
CH2NBOC, CH2NBOC, CHOH, CHOBn), 4.55 (m, 2H,
CH2Ph), 7.25 (m, 5H, C6H5). 13C NMR (CDCl3, 100 MHz):
d 152.9, 138.2, 128.4, 127.7, 127.6, 85.8, 80.1, 76.0, 73.1,
70.5, 46.2, 28.4, 26.3, 20.8. IR (Neat) (cm21): 3448, 2974,
2932, 2870, 1691, 1523, 1476, 1454, 1414, 1366, 1248,
1168, 1105, 1066, 890, 738, 699. FABMS: m/z 322 (Mþ1).
Anal. calcd for C18H27NO4: C 67.26, H 8.47, N 4.36, found:
C 67.02, H 8.25, N 4.02.
Acknowledgements
Ch. S. thanks DST and CSIR, New Delhi for financial
assistance.
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